The present invention relates to a pharmaceutical agent, particularly, a piperazine compound useful as a TNF-xcex1 production inhibitor and/or an IL-10 production promoter, and use thereof as a pharmaceutical agent.
There are a number of cytokines that have been found as proteins involved in the expression of biological functions, such as biological immune responses, inflammatory reactions and the like. Of such cytokines, tumor necrosis factor alpha (hereinafter to be referred to as TNF-xcex1) was first found as a cytokine having an anti-tumor effect. Subsequent studies have characterized it as a cytokine involved in inflammations. In recent years, TNF-xcex1 has been recognized as a cytokine broadly involved in biophylaxis through inflammation and immune responses.
For example, TNF-xcex1 has been reported to show a promoting effect on the production of interleukin-1 (hereinafter to be referred to as IL-1), which is an inflammatory cytokine, and the like, an endotoxin shock induction effect, a fibroblast proliferation effect, a bone resorption effect, and an action to cause arthritis, such as cartilage destruction effect and the like [Beutler, B., et al., Nature, 316, 552-554 (1985):Peetre, C., et al., J. Clin. Invest., 78, 1694-1700 (1986):Bevilacqua, M. P., et al., Science, 241, 1160-1165 (1989)].
In rheumatoid arthritis, TNF-xcex1 activity has been found in synovial fluid and sera [Macnaul, K. L., et al., J. Immunol., 145, 4154-4166 (1990):Brennan, F. M., et al., J. Immunol., 22, 1907-1912 (1992)]. Since an anti-TNF-xcex1 chimera antibody has been recently reported to be effective against rheumatoid arthritis and Crohn""s disease, the importance of TNF-xcex1 in these diseases has been recognized [Elliott, M. J, et al., Arthritis Rheum., 36, 1681-1690 (1993):VanDullemen, H. M. et al., Gastroenterology 109, 129-135 (1995)].
Increased TNF-xcex1 concentrations have been reported in the expectoration of patients with adult respiratory distress syndrome (ARDS), which is a serious respiratory disease, and TNF-xcex1 is considered to be involved in ARDS [Marks, J. D. et al., Am. Rev. Respir. Dis. 141, 94-97 (1990), Millar, A. B. et al., Nature, 324, 73 (1986)]. TNF-xcex1 is also considered to be involved in viral hepatitis and fulminant viral hepatitis [Sheron, N. et al., Lancet 336, 321-322 (1990), Muto, Y. et al., Lancet, ii, 72-74 (1986)].
In the case of myocardial ischemia, such as acute myocardial infarction, the TNF-xcex1 concentration in blood has been reported to increase [Latini, R., et al., J. Cardiovasc. Pharmacol., 23, 1-6 (1990)], thereby suggesting the involvement of TNF-xcex1 in such disease state [Squadrito, F. et al., Inflammation Res., 45, 14-19 (1996), Lefer, A. M. et al., Science, 249, 61-64 (1990)]. More recently, TNF-xcex1 has been reported to inhibit myocardial contraction [Finkel, M. S., et al., Science, 257, 387-389 (1992); Pagani, D. F., et al., J. Clin. Invest., 90, 389-398 (1992)].
In addition, TNF-xcex1 has been found to be equivalent to cachectin which is a cachexia inducer that hypercatabolizes the systemic metabolism in cancer and infectious diseases and causes utmost exhaustion [B. Beutler, D. Greenwald, J. D. Hulmes et al., Nature, 316, 552-554 (1985)].
TNF-xcex1 is listed as one of the causes of sepsis [Starnes, H. F. Jr. et al., J. Immunol., 145, 4185-4191 (1990), Lechner, A. J. et al., Am. J. Physiol., 263, 526-535 (1992)], and an inhibitory effect on septic shock has been acknowledged in an experiment using a TNF-xcex1 antibody [Starnes, H. F. Jr., et al., J. Immunol., 145, 4185-4191 (1990); Beutler, B., et al., Science, 229, 869-871 (1985)].
Other than the above-mentioned, possible involvement of TNF-xcex1 has been suggested in osteoarthritis [Lewis, A. J. et al., Immunopharm. Immunotoxicol., 17, 607-613 (1995), Venn, G., et al., Arthritis Rheum., 36(6), 819-826 (1993)], multiple sclerosis [Sharief, M. K., etal., Engl. J. Med., 325(7), 467-472 (1991), Beck, J. et al., Acta. Neurol. Scand., 78, 318-323 (1988), Franciotta, D. M. et al., Ann. Neurol., 26, 787-789 (1989), Hofmann, F. M. et al., J. Exp. Med., 170, 607-612 (1989), Gallo, P. et al., J. Neuroimmunol., 23, 41-44 (1989)], Kawasaki disease [Matsubara, T., et al., Clin. Immunol., Immunopathol., 56, 29-36 (1990)], inflammatory bowel diseases such as ulcerative colitis, Crohn""s disease and the like [Murch, S. et al., Arch. Dis. Child, 66, 561 (1991), Van Dullemen et al., Gastroenterology, 109, 129-135 (1995)], Behqet""s disease [Akoglu, T., et al., J. Rheumatol., 17, 1107-1108(1990)], systemic lupus erythematosus (SLE) [Maury, C. P. J., et al., Arthritis Rheum., 32, 146-150(1989)], graft versus host disease (GvHD) [Piruet et al., J. Exp. Med., 170, 655-663 (1987), Holler et al., Blood, 75, 1011-1016 (1990), Irle et al., Bone Marrow Transplant., 3, 127 (1988), Symington et al., Transplantation, 50, 518-521 (1990), Herve et al., Blood, 79, 3362-3368 (1992), Herve et al., Immunol. Rev., 129, 31-55 (1992), Nestel, F. P., et al., J. Exp. Med., 175, 405-413 (1992)], allograft rejection [Imagawa et al., Transplantation, 50, 189-193 (1990)], malaria [Grau, G. E., et al., Science, 237, 1210-1212 (1987), Grau et al., N. Engl. J. Med., 320, 1586-1591 (1989), Kwiatkowski et al., Q. J. Med., 86, 91-98 (1993)], acquired immunodeficiency syndrome (AIDS) [Lahdevirt et al., Am. J. Med., 85, 289-291 (1988), Tracy, Cancer. Cell, 1, 62-63 (1989), odeh, J. Intern. Med., 228, 549-556 (1990), Bromberg et al., J. Immunol., 148, 3412-3417 (1992), Wllaurie et al., AIDS, 6, 1265-1268 (1992), Ayehunie et al., Clin. Exp. Immunol., 91, 37-42 (1993)], meningitis [Waage, A., et al., Lancet I, 355-357(1987) diabetes [Held, W. et al., Proc. Natl. Acad. Sci. USA, 87, 2239-2243 (1990), Hotamisligil, G. S., et al., Science, 259, 87-91 (1993)], thermal burn [Marano, M. A. et al., Surg. Gynecol. Obstet., 170, 32-38 (1990)], ischemia-reperfusion injury [Squadrito, F. et al., J. Lipid Mediators 8, 53-65 (1993)], chronic heart failure [Levine, B. et al., New Engl. J. Med., 323, 236-241 (1990)], infection [Chang et al., Immunol. Infect. Dis., 2, 61-68 (1992), Harvell, J. Immunol., 143, 2894-2899 (1989), Kindler et al., Cell, 56,731-740 (1989), Liew et al., Immunology, 69, 570-573 (1990), Nakane et al., Infect. Immun., 57, 3331-3337 (1989), Nakano et al., J. Immunol., 144, 1935-1941 (1990), Opal etal., J. Infect. Dis., 161, 1148-1152 (1990)], contact dermatitis [Piguet et al., J. Exp. Med., 173, 673-679 (1991)], bacterial shock [Exley et al., Lancet, 335, 1275-1277 (1990)], endotoxemia [Beutler et al., Science, 229, 860-871 (1985)], demyelinating disease [Probert et al., Proc. Natl. Acad. Sic. U.S.A., 92, 11294-11298 (1995)], fibroid lung [Piguet et al., J. Exp. Med., 170, 655-663 (1989), Piguet et al., Nature, 344, 245-247 (1990)], osteoporosis [Ishimi et al., J. Immunol., 145, 3297-3303 (1990), MacDonald et al., Br. J. Rheumatol., 31, 149-155 (1992)], thrombus due to disseminated intravascular coagulation (DIC) and the like [Tracy et al., Surg. Gen. Obstet., 164, 415-422 (1987), Van et al., N. Engl. J. Med., 322, 1622-1629 (1990)] and the like.
Interleukin-10 (hereinafter to be referred to as IL-10) is a cytokine mainly produced by type 2 helper T cells. IL-10 potentiates activity of B cells and mast cells, but for macrophages, it is one of the inhibitory cytokines that strongly inhibit the function of type 1 helper T cell involved in cellular immunity, because they inhibit antigen presenting ability or cytokine (TNF-xcex1, IL-1 and the like) production capability of macrophages. Thus, IL-10 plays an important role in the immune response system. For example, IL-10 has been reported to inhibit TNF-xcex1 production by joint synovial cells in rheumatoid arthritis [Isomaki, P, et al., Arthritis Rheum., 39, 386-395 (1996)]. It has been also reported that, when IL-10 is intravenously injected to a healthy subject and hemocytes of the subject are stimulated by endotoxin, TNF-xcex1 production is inhibited [Chernoff, A.E, et al., J. Immunol., 154, 5492-5499 (1995)]. Moreover, a report has been documented that, in IL-10 gene knockout mice, chronic colitis spontaneously occurs and, when compared to normal mice, inflammatory cytokine (TNF-xcex1, IL-1 and the like) concentration in colon tissue significantly increases, but that administration of IL-10 inhibits incidence of colitis and progress of the disease [Breg D. J. et al., J. Clin. Invest., 98, 1010 (1996)]. In the tumor cells, into which IL-10 gene has been transferred, the tumor growth can be inhibited and metastasis of the tumor can be also inhibited [Kundu N. et al., Int. J. Cancer, 76, 713 (1998)]. At present, a gene recombinant human IL-10 has been under development as a therapeutic drug of septic shock, Crohn""s disease, rheumatoid arthritis and malignant tumor.
JP-A-52-156879 discloses a piperazine derivative useful as an analgesic and antiphlogistic agent, psychotropic, antianxiety drug and hypotensive agent, and JP-A-9-208570 discloses a benzylpiperazine derivative useful as an anti-allergic agent and anti-inflammatory agent. U.S. Pat. No. 5,569,659 discloses a 4-arylpiperazine compound and a 4-arylpiperidine compound useful as an antipsychotic drug, and J. Med. Chem., vol. 38, pp. 4211-4222 (1995) discloses an N-aryl-Nxe2x80x2-benzylpiperazine compound which is useful as an antipsychotic drug. Moreover, WO92/12154 discloses an imidazotriazine compound, and WO94/19350 discloses a pyrazolotriazine compound, respectively as an IL-1 and TNF-xcex1 production inhibitor.
As mentioned above, it has become clear that hyperproduction of TNF-xcex1 causes intense effect on normal cells and various disease states. Thus, a TNF-xcex1 production inhibitor that can cure such disease states has been desired. However, the anti-TNF-xcex1 antibody currently under development is associated with therapeutic problems such as availability only as an injection, easy generation of antibody and the like, and therefore, it is not entirely satisfactory as a TNF-xcex1 production inhibitor.
A pharmaceutical agent that promotes the production of IL-10 is expected to be a therapeutic agent of the diseases in which TNF-xcex1 is involved, because IL-10 inhibits production of TNF-xcex1. However, such pharmaceutical agent is not commercially available at the moment. A gene recombinant human IL-10 now being developed is a biological preparation, which is subject to therapeutic problems such as availability only as an injection, easy generation of antibody and the like, as in the case of anti-TNF-xcex1 antibody, and therefore, it is insufficient.
The compound disclosed in the above-mentioned JP-A-52-156879 has lower alkylene between phenyl and piperazine ring wherein the lower alkylene may be methylene, ethylene, propylene, trimethylene or ethylidene. Specific examples include only the compounds wherein lower alkylene is ethylene or propylene. These disclosed compounds have an analgesic and antiphlogistic effect but simultaneously have an effect on the central nervous system. Because of the side effects due to the effect on the central nervous system, the development of the compound as an analgesic or antiphlogistic agent is difficult. In addition, the compounds disclosed in WO92/12154 and WO94/19350 do not show sufficient TNF-xcex1 production inhibitory effect, and are not satisfactory.
It is therefore an object of the present invention to provide a compound which has a superior TNF-xcex1 production inhibitory effect and/or IL-10 production promoting effect, has no effect on the central nervous system, and which is useful for the prophylaxis or treatment of autoimmune diseases, inflammatory diseases and the like.
The present inventors have conducted intensive studies with the purpose of solving the above-mentioned problems and found that, of the compounds described in JP-A-52-156879, a compound wherein lower alkylene between phenyl and piperazine ring is methylene or methylene substituted by lower alkyl, which compound is not concretely disclosed therein, has superior TNF-xcex1 production inhibitory effect and/or IL-10 production promoting effect and is free of or shows only strikingly reduced expression of an effect on the central nervous system, which resulted in the completion of the present invention.
Accordingly, the present invention provides the following.
(1) A piperazine compound of the formula 
wherein
R1 and R2 are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy, amino, amino mono- or di-substituted by a group selected from the group consisting of lower alkyl and lower acyl, nitro, hydroxy or cyano;
R3, R4 and R5 are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amino, hydroxy or amino mono- or di-substituted by a group selected from the group consisting of lower alkyl and lower acyl;
R6 and R7 are the same or different and each is hydrogen, lower alkyl, lower alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl or lower acyl substituted by 1 to 3 halogen(s);
R8 and R9 are the same or different and each is hydrogen or lower alkyl;
Y is a group of the formula 
wherein R10 and R11 are the same or different and each is hydrogen or lower alkyl, R12 and R13 are the same or different and each is hydrogen or lower alkyl, or R12 and R13 in combination form alkylene, R14 and R15 are the same or different and each is hydrogen or lower alkyl, m is an integer
of 0-2, n is an integer of 0-2, and 0xe2x89xa6m+nxe2x89xa62; and ring A is phenyl, pyrimidyl, thiazolyl, pyridyl, pyrazyl or imidazolyl,
provided that when one of R6 and R7 is hydrogen and the other is butyl, in Y, both R12 and R13 are hydrogen, m and n are 0, R1, R2, R8 and R9 are hydrogen, and ring A is phenyl, one of R3, R4 and R5 should not be 2-isopropoxy and the remaining two should not be hydrogen,
and a pharmaceutically acceptable salt thereof.
(2) The piperazine compound of the above-mentioned (1), which has the following formula 
wherein
R1 and R2 are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy, amino, amino mono- or di-substituted by a group selected from the group consisting of lower alkyl. and lower acyl, nitro, hydroxy or cyano;
R3, R4 and R5 are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amino, hydroxy or amino mono- or di-substituted by a group selected from the group consisting of lower alkyl and lower acyl;
R6 and R7 are the same or different and each is hydrogen, lower alkyl, lower alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl or lower acyl substituted by 1 to 3 halogen(s); and
Y1 is a group of the formula 
wherein R12 and R13 are the same or different and each is hydrogen or lower alkyl, or R12 and R13 in combination form alkylene,
provided that when one of R6 and R7 is hydrogen and the other is butyl, in Y1, both R12 and R13 are hydrogen and R1 and R2 are hydrogen, one of R3, R4 and R5 should not be 2-isopropoxy and the remaining two should not be hydrogen,
and a pharmaceutically acceptable salt thereof.
(3) The piperazine compound of the above-mentioned (1), which has the following formula 
wherein
R1 and R2 are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy, amino, amino mono- or di-substituted by a group selected from the group consisting of lower alkyl and lower acyl, nitro, hydroxy or cyano;
R3, R4 and R5 are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amino, hydroxy or amino mono-or di-substituted by a group selected from the group consisting of lower alkyl and lower acyl;
R6 and R7 are the same or different and each is hydrogen, lower alkyl, lower alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl or lower acyl substituted by 1 to 3 halogen(s);
R8a is lower alkyl; and
Y1 is a group of the formula 
wherein R12 and R13 are the same or different and each is hydrogen or lower alkyl, or R12 and R13 in combination form alkylene,
and a pharmaceutically acceptable salt thereof.
(4) The piperazine compound of the above-mentioned (3), wherein-R8a is methyl and a pharmaceutically acceptable salt thereof.
(5) The piperazine compound of the above-mentioned (1), which has the following formula 
wherein
R1 and R2 are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy, amino, amino mono-or di-substituted by a group selected from the group consisting of lower alkyl and lower acyl, nitro, hydroxy or cyano;
R3, R4 and R5 are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amino, hydroxy or amino mono-or di-substituted by a group selected from the group consisting of lower alkyl and lower acyl;
R6 and R7 are the same or different and each is hydrogen, lower alkyl, lower alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl or lower acyl substituted by 1 to 3 halogen(s);
R8a and R9a are the same or different and each is lower alkyl; and
Y1 is a group of the formula 
wherein R12 and R13 are the same or different and each is hydrogen or lower alkyl, or R12 and R13 in combination form alkylene,
and a pharmaceutically acceptable salt thereof.
(6) The piperazine compound of the above-mentioned (5), wherein R8a and R9a are both methyl, and a pharmaceutically acceptable salt thereof.
(7) The piperazine compound of any of the above-mentioned (1) to (6), wherein R3, R4 and R5 are the same or different and each is hydrogen, halogen or lower alkoxy, and a pharmaceutically acceptable salt thereof.
(8) The piperazine compound of the above-mentioned (1), which has the following formula 
wherein
R1 and R2 are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy, amino, amino mono-or di-substituted by a group selected from the group consisting of lower alkyl and lower acyl, nitro, hydroxy or cyano;
ring Axe2x80x2 is a group of the formula 
wherein R16 and R17 are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy or amino mono- or di-substituted by a group selected from the group consisting of lower alkyl and lower acyl, and R18 is hydrogen or lower alkyl;
R6 and R7 are the same or different and each is hydrogen, lower alkyl, lower alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl or lower acyl substituted by 1 to 3 halogen(s); and
Y1 is a group of the formula 
wherein R12 and R13 are the same or different and each is hydrogen or lower alkyl, or R12 and R13 in combination form alkylene,
and a pharmaceutically acceptable salt thereof.
(9) The piperazine compound of the above-mentioned (1), which has the following formula 
wherein
R1 and R2 are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy, amino, amino mono- or di-substituted by a group selected from the group consisting of lower alkyl and lower acyl, nitro, hydroxy or cyano;
ring Axe2x80x2 is a group of the formula 
wherein R16 and R17 are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy, amino mono- or di-substituted by a group selected from the group consisting of lower alkyl and lower acyl, and R18 is hydrogen or lower alkyl;
R6 and R7 are the same or different and each is hydrogen, lower alkyl, lower alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl or lower acyl substituted by 1 to 3 halogen(s);
R8a is lower alkyl; and
Y1 is a group of the formula 
wherein R12 and R13 are the same or different and each is hydrogen or lower alkyl, or R12 and R13 in combination form alkylene,
and a pharmaceutically acceptable salt thereof.
(10) The piperazine compound of the above-mentioned (9), wherein R8a is methyl, and a pharmaceutically acceptable salt thereof.
(11) The piperazine compound of the above-mentioned (1), which has the following formula 
wherein
R1 and R2 are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy, amino, amino mono- or di-substituted by a group selected from the group consisting of lower alkyl and lower acyl, nitro, hydroxy or cyano;
ring Axe2x80x2 is a group of the formula 
wherein R16 and R17 are the same or different and each is hydrogen,
halogen, lower alkyl, lower alkoxy or amino mono- or di-substituted by a group selected from the group consisting
of lower alkyl and lower acyl, and R18 is hydrogen or lower alkyl;
R6 and R7 are the same or different and each is hydrogen, lower alkyl, lower alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl or lower acyl substituted by 1 to 3 halogen(s);
R8a and R9a are the same or different and each is lower alkyl; and
Y1 is a group of the formula 
wherein R12 and R13 are the same or different and each is hydrogen or lower alkyl, or R12 and R13 in combination form alkylene,
and a pharmaceutically acceptable salt thereof.
(12) The piperazine compound of the above-mentioned (11), wherein R8a and R9a are both methyl, and a pharmaceutically acceptable salt thereof.
(13) The piperazine compound of any of the above-mentioned (1) to (12), wherein one of R6 and R7 is hydrogen and the other is acyl, and a pharmaceutically acceptable salt thereof.
(14) The piperazine compound of any of the above-mentioned (1) to (13), wherein R12 and R13 are the same or different and each is hydrogen or methyl, R12 and R13 in combination form ethylene, and a pharmaceutically acceptable salt thereof.
(15) The piperazine compound of the above-mentioned (1), (2), (7), (13) or (14), which is a member selected from the group consisting of N-(4-((4-phenylpiperazin-1-yl)methyl)phenylmethyl)acetamide, N-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)-acetamide, N-(4-((4-(2-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)-acetamide, N-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)phenylmethyl)-acetamide, N-(2-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)ethyl)acetamide, N-(2-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)-acetamide, N-(1-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)ethyl)acetamide, N-(1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)-acetamide, N-(1-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)phenyl)-ethyl)acetamide, N-(1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)-1-methylethyl)acetamide, N-(1-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)cyclopropyl)-acetamide and N-(1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)-cyclopropyl)acetamide,
and a pharmaceutically acceptable salt thereof.
(16) The piperazine compound of the above-mentioned (1), (3), (4), (7),
(13) or (14), which is a member selected from the group consisting of N-(4-(1-( 4-phenylpiperazin-1-yl) ethyl)phenylmethyl )acetamide, N-(4-(1-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)phenylmethyl)-acetamide and N-(4-(1-(4-(2,4-difluorophenyl)piperazin-1-yl)ethyl)phenylmethyl)-acetamide,
and a pharmaceutically acceptable salt thereof.
(17) The piperazine compound of the above-mentioned (1), (5)-(7), (13) or (14), which is N-(4-(1-(4-(4-fluorophenyl)piperazin-1-yl)-1-methylethyl) phenylmethyl) acetamide, and a pharmaceutically acceptable salt thereof.
(18) The piperazine compound of the above-mentioned (1), (7), (8), (13) or (14), which is a member selected from the group consisting of N-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)-acetamide, N-(1-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)-acetamide, N-(1-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)-cyclopropyl)acetamide, N-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)-formamide, N-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)-propionamide, N-(4-((4-(thiazol-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide and N-(4-((4-(pyridin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide,
and a pharmaceutically acceptable salt thereof.
(19) The piperazine compound of the above-mentioned (1), (7), (9), (10), (13) or (14), which is N-(1-(4-(1-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)phenyl)cyclopropyl)acetamide, and a pharmaceutically acceptable salt thereof.
(20) A pharmaceutical composition containing the piperazine compound of any of the above-mentioned (1) to (19) or a pharmaceutically acceptable salt thereof as an active ingredient.
(21) A TNF-xcex1 production inhibitor and/or IL-10 production promoter containing the piperazine compound of any of the above-mentioned (1) to (19) or a pharmaceutically acceptable salt thereof as an active ingredient.
(22) An agent for the prophylaxis or treatment of diseases caused by abnormal TNF-xcex1 production, TNF-xcex1 mediated diseases or diseases curable with IL-10, which contains the piperazine compound of any of the above-mentioned (1) to (19) or a pharmaceutically acceptable salt thereof as an active ingredient.
(23) An agent for the prophylaxis or treatment of an inflammatory disease, which contains the piperazine compound of any of the above-mentioned (1) to (19) or a pharmaceutically acceptable salt thereof as an active ingredient.
(24) An agent for the prophylaxis or treatment of an autoimmune disease, which contains the piperazine compound of any of the above-mentioned (1) to (19) or a pharmaceutically acceptable salt thereof as an active ingredient.
(25) An agent for the prophylaxis or treatment of rheumatoid arthritis, which contains the piperazine compound of any of the above-mentioned (1) to (19) or a pharmaceutically acceptable salt thereof as an active ingredient.
(26) An agent for the prophylaxis or treatment of an allergic disease, which contains the piperazine compound of any of the above-mentioned (1) to (19) or a pharmaceutically acceptable salt thereof as an active ingredient.
The groups shown by respective symbols in the specification are explained in the following.
Halogen at R1 and R2 is fluorine, chlorine, bromine or iodine.
Lower alkyl at R1 and R2 is alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like.
Lower alkoxy at R1 and R2 is alkoxy having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and the like.
With regard to the amino mono- or di-substituted by a group selected from lower alkyl and lower acyl at R1 and R2, lower alkyl as a substituent means alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like. Lower acyl as a substituent means lower alkanoyl having 1 to 4 carbon atoms, lower alkoxycarbonyl having 1 to 4 carbon atoms or C1-C4 lower alkanoyl substituted by phenyl. Examples thereof include formyl, acetyl, propionyl, butyryl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, benzoyl, phenylacetyl and phenylpropionyl. Amino mono- or di-substituted by these substituents means methylamino, dimethylamino, ethylamino, diethylamino, propylamino, butylamino, acetylamino, diacetylamino, propionylamino, dipropionylamino, butyrylamino, N-methyl-N-acetylamino, N-ethyl-N-acetylamino, N-methyl-N-propionylamino, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, tert-butoxycarbonylamino, benzoylamino, phenylacetylamino and the like.
Halogen at R3, R4 and R5 is fluorine, chlorine, bromine or iodine.
Lower alkyl at R3, R4and R5 means alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like.
Lower alkoxy at R3, R4 and R5 means alkoxy having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and the like.
With regard to the amino mono- or di-substituted by a group selected from lower alkyl and lower acyl at R3, R4 and R5, lower alkyl as a substituent means alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like. Lower acyl as a substituent means lower alkanoyl having 1 to 4 carbon atoms, lower alkoxycarbonyl having 1 to 4 carbon atoms or C1-C4 lower alkanoyl substituted by phenyl. Examples thereof include formyl, acetyl, propionyl, butyryl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, benzoyl, phenylacetyl and phenylpropionyl. The amino mono- or di-substituted by these substituents may be methylamino, dimethylamino, ethylamino, diethylamino, propylamino, butylamino, acetylamino, diacetylamino, propionylamino, dipropionylamino, butyrylamino,- N-methyl-N-acetylamino, N-ethyl-N-acetylamino, N-methyl-N-propionylamino, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, tert-butoxycarbonylamino, benzoylamino, phenylacetylamino and the like.
Lower alkyl at R6 and R7 means alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like.
The lower alkyl substituted by 1 to 3 halogen(s) at R6 and R7 is
C1-C4 lower alkyl substituted by halogen (e.g., fluorine, chlorine, bromine and the like). Examples thereof include fluoromethyl, trifluoromethyl, chloromethyl, bromomethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloroethyl, 2-bromoethyl, 3-fluoropropyl, 3-chloropropyl, 4-fluorobutyl, 4-chlorobutyl and the like.
Aralkyl at R6 and R7 means benzyl, 2-phenylethyl, 3-phenylpropyl.
Acyl at R6 and R7 means alkanoyl having 1 to 5 carbon atoms, lower alkoxycarbonyl having 1 to 4 carbon atoms, C1-C4 lower alkanoyl substituted by phenyl or pyridyl, or C1-C4 lower alkylsulfonyl. Examples thereof include formyl, acetyl, propionyl, butyryl, valeryl, isovaleryl, trimethylacetyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, benzoyl, nicotinoyl, isonicotinoyl, picolinoyl, phenylacetyl, phenylpropionyl, methanesulfonyl and the like.
Lower acyl substituted by 1 to 3 halogen(s) at R6 and R7 is C1-C4 lower acyl substituted by halogen (e.g., fluorine, chlorine, bromine and the like). Examples thereof include fluoroacetyl, trifluoroacetyl, chloroacetyl, bromoacetyl, 3-chloropropionyl, 3-bromopropionyl, 4-chlorobutyryl, 4-bromobutyryl and the like.
Lower alkyl at R8 and R9 means alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like.
Lower alkyl at R10 and R11 means alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl and the like.
Lower alkyl at R12 and R13 means alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl and the like.
The alkylene formed by R12 and R13 in combination means methylene, ethylene, trimethylene, tetramethylene, pentamethylene.
Lower alkyl at R14 and R15 means alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl and the like.
Halogen at R16 and R17 means fluorine, chlorine, bromine or iodine.
Lower alkyl at R16 and R17 means alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like. Lower alkoxy at R16 and R17 means alkoxy having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and the like.
With regard to the amino mono- or di-substituted by a group selected from lower alkyl and lower acyl at R16 and R17, lower alkyl as a substituent means alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like. Lower acyl as a substituent means lower alkanoyl having 1 to 4 carbon atoms, lower alkoxycarbonyl having 1 to 4 carbon atoms or C1-C4 lower alkanoyl substituted by phenyl. Examples thereof include formyl, acetyl, propionyl, butyryl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, benzoyl, phenylacetyl and phenylpropionyl. The amino mono- or di-substituted by these substituents is exemplified by methylamino, dimethylamino, ethylamino, diethylamino, propylamino, butylamino, acetylamino, diacetylamino, propionylamino, dipropionylamino, butyrylamino, N-methyl-N-acetylamino, N-ethyl-N-acetylamino, N-methyl-N-propionylamino, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, tert-butoxycarbonylamino, benzoylamino, phenylacetylamino and the like.
Lower alkyl at R18 means alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like.
Ring A is 
wherein each symbol is as defined in the above. Ring Axe2x80x2 is 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazyl or 2-imidazolyl, mentioned above, with preference given to the above-mentioned 2-pyrimidyl, 2-thiazolyl, 2-pyridyl or 2-imidazolyl.
The pharmaceutically acceptable salt of the compound (I) of the present invention is, for example, a salt with inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like, a salt with organic acid such as acetic acid, maleic acid, fumaric acid, benzoic acid, citric acid, succinic acid, tartaric acid, malic acid, mandelic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid and the like. The compound of the present invention can be converted to a quaternary ammonium salt. The compound of the present invention (I) and a pharmaceutically acceptable salt thereof may be a hydrate (monohydrate, 1/2 hydrate, 1/4 hydrate, 1/5 hydrate, dihydrate, 3/2 hydrate, 3/4 hydrate and the like) or a solvate. When the inventive compound (I) has an asymmetric carbon, at least two optical isomers exist. The present invention encompasses these optical isomers and racemates thereof.
The compound of the present invention can be produced by, for example, the following methods.
Method A 
wherein Lv is a leaving group widely used in the organic synthetic chemistry, suchas halogen (e.g, fluorine, chlorine, bromineor iodine), mnethanesulfonyloxy, p-toluenesulfonyloxy and trifluoromethane-sulfonyloxy, P1 and P2 encompass R6 and R7 defined earlier, and further mean an amino-protecting group widely used in the organic synthetic chemistry, such as benzyloxycarbonyl, P1and P2 may form an imido group, such as phthalimide, together with the adjacent nitrogen atom and other symbols are as defined above. When R3, R4 and R5 have a functional group such as amino, hydroxy and the like, they may be protected as necessary.
The base to be used for the condensation of compound (II) and compound (III) may be, for example, potassium carbonate, potassium hydrogencarbonate, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium hydride, lithium diisopropylamide, butyl lithium, lithium hexamethyldisilazane, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, pyridine and 4-dimethylaminopyridine.
The solvent to be used for the condensation may be, for example, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether, benzene, dichloromethane, dichloroethane, chloroform, toluene, xylene, hexane, dimethylformamide, dimethyl sulfoxide, water and a mixture thereof.
The reaction temperature of condensation is generally from xe2x88x9280xc2x0 C. to 150xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of condensation is generally from 30 minutes to 2 days, and a time longer or shorter than this range can be employed as necessary.
After condensation under the above-mentioned reaction conditions, a protecting group(s) is/are removed as necessary, after which compound (I) can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
The compound (III) may be a commercially available one or may be synthesized from bis(2-chloro or bromoethyl)amine and substituted aromatic amine according to the method disclosed in Journal of Medicinal Chemistry (J. Med. Chem.), vol. 29, pp. 630-634 (1986) or Tetrahedron Letters, vol. 37, pp. 319-322 (1996). Alternatively, it can be synthesized by treating bis(2-hydroxyethyl)amine and substituted aromatic amine in an aqueous hydrochloric acid solution.
Method B
Compound (I) wherein one of R6 and R7 is acyl and the other is hydrogen is hydrolyzed to give compound (I-1) wherein R6 and R7 of compound (I) are hydrogen 
wherein each symbol is as defined above.
Hydrolysis can be performed under both acidic conditions and basic conditions. When acidic conditions are employed, mineral acid (e.g., hydrochloric acid, sulfuric acid and the like), preferably a concentrated or diluted aqueous hydrochloric acid solution, is used and, Cas an organic co-solvent, for example, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, acetonitrile or a mixture thereof is used. When basic conditions are employed, the base to be used may be, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide or barium hydroxide. The solvent used may be, for example, water, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, acetonitrile or a mixture thereof.
The reaction temperature of hydrolysis is generally from xe2x88x9220xc2x0 C. to 150xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of hydrolysis is generally from 30 minutes to 2 days, and a time longer or shorter than this range can be employed as necessary.
After hydrolysis under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), compound (I-1) can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
The methods (Method B1 to Method B8) for modifying the amino group of compound (I-1) are explained in the following.
Method B1
wherein Ra is C1-C4 alkyl optionally substituted by 1 to 3 halogen(s) (e.g., fluorine, chlorine, bromine and the like), Hal is halogen (e.g., chlorine, bromine, iodine and the like), Rb is C1-C4 alkyl optionally substituted by 1 to 3 halogen(s) (e.g., fluorine, chlorine, bromine and the like), Rc is C1-C4 alkyl optionally substituted by 1 to 3 halogen(s) (e.g., fluorine, chlorine, bromine and the like), and the other symbols are as defined above.
The base to be used for condensation of compound (I-1) may be, for example, triethylamine, diisopropylethylamine, potassiumcarbonate, potassium hydrogencarbonate, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, sodiummethoxide, sodium ethoxide, pyridine and 4-dimethylaminopyridine.
The solvent to be used for condensation may be, for example, water, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether, benzene, dichloromethane, dichloroethane, chloroform, ethyl acetate, toluene, xylene, hexane, dimethylformamide, dimethyl sulfoxide and a mixture thereof.
The reaction temperature of condensation is generally from xe2x88x9220xc2x0 C. to 80xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of condensation is generally from 30 minutes to 2 days, and a time longer or shorter than this range can be employed as necessary.
After reduction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), compound (I-2) can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method B2
wherein each symbol is as defined above.
The reducing agent to be used for reduction of amide group in compound (I-2) may be, for example, metallic reducing reagent such as aluminum lithium hydride, sodium borohydride, lithium borohydride and the like, or diborane.
The solvent to be used for reduction of amide group may be, for example, tetrahydrofuran, dioxane, diethyl ether, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, ethylene glycol dimethyl ether, a mixture thereof and the like.
The reaction temperature of reduction of amino group is generally from xe2x88x9220xc2x0 C. to 80xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of reduction of amide group is generally from 30 minutes to 10 hours, and a time longer or shorter than this range can be employed as necessary.
After reduction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), compound (I-3) can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method B3
Compound (I-3) can be also produced by the following method. 
wherein each symbol is as defined above.
The reducing agent to be used for reductive amination of compound (I-1) may be, for example, sodium borohydride or sodium cyanoborohydride, and catalytic reduction using transition metal (e.g., palladium-carbon, platinum oxide, Raney nickel, rhodium, ruthenium) is also effective.
The solvent to be used for reductive amination may be, for example, water, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether, acetone, ethyl acetate, acetic acid, benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide or a mixture thereof.
The reaction temperature of reductive amination is generally from xe2x88x9220xc2x0 C. to 150xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of reductive amination is generally from 30 minutes to 2 days, and a time longer or shorter than this range can be employed as necessary.
After reduction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), compound (I-3) can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method B4
wherein Rd is hydrogen or C1-C4 alkyl optionally substituted by 1 to 3 halogen(s) (e.g., fluorine, chlorine, bromine and the like), and the other symbols are as defined above.
The reaction conditions (reagent, reaction solvent, reaction time) of acylation are the same as in Method B1.
After acylation under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), compound (I-4) can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method B5
wherein each symbol is as defined above.
The reaction conditions (reagent, reaction solvent, reaction time) of reduction are the same as in Method B2.
After reduction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), compound (I-5) can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin. Method B6
wherein Re is C1-C4 alkyl optionally substituted by 1 to 3 halogen(s) (e.g., fluorine, chlorine, bromine and the like), and the other symbols to are as defined above.
In this reaction, the acyl moiety (Rcxe2x80x94Cxe2x95x90O) is preferably electron-withdrawing group such as trifluoroacetyl and the like.
The base to be used for condensation of compound (I-2) may be, for example, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium hydride, lithium diisopropylamide, butyl lithium, phenyl lithium, lithium hexamethyldisilazane, triethylamine, diisopropylethylamine or 1,8-diazabicyclo[5.4.0]undeca-7-ene.
The solvent to be used for condensation may be, for example, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether, dichloromethane, dichloroethane, chloroform, benzene, toluene, xylene, hexane, dimethylformamide, dimethyl sulfoxide or a mixture thereof.
The reaction temperature of condensation is generally from xe2x88x9280xc2x0 C. to 150xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of condensation is generally from 30 minutes to 2 days, and a time longer or shorter than this range can be employed as necessary.
After condensation under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), compound (I-6) can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method B7
wherein each symbol is as defined above.
Hydrolysis is performed under the same reaction conditions as in Method B.
After hydrolysis under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), compound (I-7) can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method B8
wherein each symbol is as defined above.
The reduction is performed under the same reaction conditions as in Method B2.
After reduction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), compound (I-5a) can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method C
Compound (I) can be also produced by the following method. 
wherein each symbol is as defined above.
The reaction conditions (reagent, reaction solvent, reaction time) of condensation are the same as in the condensation in Method A.
After condensation under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), compound (I) can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method D
Compound (I-1) can be also produced by the following method. 
wherein each symbol is as defined above.
The metal azide compound to be used for the azidation of compound (VIII) is exemplified by sodium azide, lithium azide and the like.
The solvent to be used for azidation may be, for example, water, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether, acetone, ethyl acetate, acetic acid, benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide or a mixture thereof.
The reaction temperature of azidation is generally from 0xc2x0 C. to 150xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of azidation is generally from 30 minutes to 2 days, and a time longer or shorter than this range can be employed as necessary.
The reducing agent to be used for reduction of the azide group in compound (X) may be, for example, a metallic reducing reagent such as aluminum lithium hydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride and the like, diborane or triphenylphosphine, and catalytic reduction using transition metal (e.g., palladium-carbon, platinum oxide, Raney nickel, rhodium, ruthenium) is also effective.
The solvent to be used for reduction of the azide group may be, for example, water, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether, acetone, ethyl acetate, acetic acid, benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide or a mixture thereof.
The reaction temperature of reduction of the azide group is generally from xe2x88x9220xc2x0 C. to 150xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of reduction of the azide group is generally from 30 minutes to 2 days, and a time longer or shorter than this range can be employed as necessary.
After each reaction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), the synthetic intermediate in each step and the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method E
Compound (I-1) can be also produced by the following method. 
wherein each symbol is as defined above.
The solvent to be used for condensation of compound (VIII) may be, for example, water, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether, acetone, ethyl acetate, acetic acid, benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide or a mixture thereof.
The reaction temperature of condensation is generally from 0xc2x0 C. to 150xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of condensation is generally from 30 minutes to 2 days, and a time longer or shorter than this range can be employed as necessary.
The base to be used for cleavage of compound (XI) may be, for example, hydrazine hydrate, methyl hydrazine, phenyl hydrazine, sodium hydroxide, potassium hydroxide, barium hydroxide or lithium hydroxide.
The solvent to be used for cleavage may be, for example, water, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether, acetone, dimethylformamide, dimethyl sulfoxide or a mixture thereof.
The reaction temperature of cleavage is generally from 0xc2x0 C. to 150xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of cleavage is generally from 30 minutes to 2 days, and a time longer or shorter than this range can be employed as necessary.
After each reaction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), the synthetic intermediate in each step and the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method F
Compound (XI) can be also produced by the following method. 
wherein each symbol is as defined above.
The reagent to be used for Mitsunobu reaction may be, for example, dialkyl azodicarboxylate (wherein alkyl means lower alkyl such as ethyl, propyl, isopropyl, butyl, isobutyl and the like) and triphenylphosphine.
The solvent to be used for Mitsunobu reaction may be, for example, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether, acetone, dimethylformamide, dimethyl sulfoxide or a mixture thereof.
The reaction temperature of Mitsunobu reaction is generally from xe2x88x9280xc2x0 C. to 100xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of Mitsunobu reaction is generally from 30 minutes to 2 days, and a time longer or shorter than this range can be employed as necessary.
After Mitsunobu reaction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), compound (XI) can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method G
Compound (I) can be also produced by the following method. 
wherein Q is the aforementioned leaving group, Lv and its precursor hydroxyl group with or without protection with a suitable protecting group, which can be easily converted to Lv by a method known in the field of organic synthetic chemistry, and other symbols are as defined above.
The reaction conditions of the condensation of compound (XIII) and compound (IX) are the same as in the conditions for Method C, Method D and Method E. The group Q of the obtained compound (XIV) is converted to a leaving group Lv as necessary by a method known in the field of organic synthetic chemistry, and condensed with compound (III) in the same manner as in Method A, which is followed by, where necessary, removal of protecting group(s) to produce compound (I).
After each reaction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), the synthetic intermediate in each step and the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method H
Compound (I) can be also produced by the following method. 
wherein each symbol is as defined above.
The reaction conditions of the condensation of compound (XV) and compound (III) are the same as in the conditions for Method A. The group Q of the obtained compound (XVI) is converted to a leaving group Lv by a method known in the field of organic synthetic chemistry. Then, in the same manner as in Method C, Method D and Method E, it is condensed with compound (IX) and, where necessary, the protecting group(s) is/are removed to produce compound (I).
After each reaction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), the synthetic intermediate in each step and the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method I
Compound (I) can be also produced by the following method. 
wherein each symbol is as defined above.
The reaction conditions (reagent, reaction solvent, reaction time) of condensation of compound (II) and compound (XVII) are the same as in Method A.
The group Q of the obtained compound (XVIII) is converted to a leaving group Lv as necessary by a method known in the field of organic synthetic chemistry. In the same manner as in Method A, it is condensed with compound (XIX) and, where necessary, the protecting group(s) is/are removed to produce compound (I).
After each reaction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), the synthetic intermediate in each step and the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method J
Compound (I) can be also produced by the following method. 
wherein each symbol is as defined above.
The reaction conditions (reagent, reaction solvent, reaction time) of condensation in this method are the same as in Method A.
After condensation under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), compound (I) can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
The compound (XXI) can be produced by condensing compound (XIX) with compound (XXIIa) 
wherein Q, Hal and R are as defined above, in the same manner as in Method A to give compound (XXIIb) (wherein each symbol is as defined above), and converting the group Q of compound (XXIIb) to a leaving group Lv as necessary by a method known in the field of organic synthetic chemistry. The compound (XXIIb) can be produced by condensing compound (XIX) with compound (XXIIc) (wherein R is lower alkyl having 1 to 4 carbon atoms and Hal is as defined above) in the same manner as in Method A to give compound (XXIId) (wherein each symbol is as defined above), and converting the resulting compound by a method known in the field of organic synthetic chemistry.
The reaction conditions (reagent, reaction solvent, reaction time) of condensation are the same as in Method A.
The reducing agent to be used for reduction of the ester group in compound (XXIId) may be, for example, a metallic reducing reagent such as aluminum lithium hydride, sodium borohydride, lithium borohydride and the like, or diborane.
The solvent to be used for reduction of the ester group may be, for example, tetrahydrofuran, dioxane, diethyl ether, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, ethylene glycol dimethyl ether or a mixture thereof.
The reaction temperature of reduction of the ester group is generally from xe2x88x9220xc2x0 C. to 80xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of reduction of the ester group is generally from 30 minutes to 10 hours, and a time longer or shorter than this range can be employed as necessary.
After reduction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), compound (XXIIb) can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method K
Compound (I) can be also produced by the following method. 
wherein Lv1 is a leaving group widely used in aromatic nucleophilic substitution reaction, such as halogen (e.g., fluorine, chlorine, bromine or iodine), nitro, p-toluenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfenyl, benzenesulfonyl, azido, aryloxy, alkoxy, alkylthio or amino, and the other symbols are as defined above.
The solvent to be used for aromatic nucleophilic substitution reaction of compound (XXIII) may be, for example, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether, benzene, dichloromethane, dichloroethane, chloroform, toluene, xylene, hexane, dimethylformamide, dimethyl sulfoxide, acetonitrile or a mixture thereof.
For aromatic nucleophilic substitution reaction, a catalyst such as copper powder, copper oxide and the like can be added as necessary.
The reaction temperature of aromatic nucleophilic substitution reaction is generally from 0xc2x0 C. to 150xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of aromatic nucleophilic substitution reaction is generally from 30 minutes to 2 days, and a time longer or shorter than this range can be employed as necessary.
After aromatic nucleophilic substitution reaction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), compound (I) can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method L
Compound (II) wherein R8 and R9 are both hydrogen can be produced by the following method. 
wherein W is carboxylic acid derivative that can be easily converted to each other by a method basic and widely used in the field of organic synthetic chemistry, such as carboxylic acid, carboxylic acid ester (COOR; wherein R is lower alkyl having 1 to 4 carbon atoms), carboxamide or carbonitrile, and the other symbols are as defined above.
The compound (XXV) is converted to an ester group as necessary by a method known in the field of organic synthetic chemistry and subjected to reduction.
The reducing agent to be used for reduction of the ester group may be, for example, a metallic reducing reagent (e.g., aluminum lithium hydride, sodium borohydride, lithium borohydride and the like) or diborane.
The solvent to be used for reduction of the ester group may be, for example, water, tetrahydrofuran, dioxane, diethyl ether, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, ethylene glycol dimethyl ether, a mixture thereof, and the like.
The reaction temperature of reduction of the ester group is generally from xe2x88x9220xc2x0 C. to 80xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of reduction of the ester group is generally from 30 minutes to 10 hours, and a time longer or shorter than this range can be employed as necessary.
After reduction under the above-mentioned reaction conditions, the hydroxyl group of compound (XXVI) is converted to a group Lv by a method known in the field of organic synthetic chemistry, and where necessary, the protecting group(s) is/are removed. The compound (II-a) can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
The compound (II-a) and compound (III) are condensed in the same manner as in Method A, and, where necessary, the protecting group(s) is/are removed to give compound (I) wherein RB and R9 are both hydrogen, namely, compound (I-8) 
wherein each symbol is as defined above.
Method M
Compound (XIV) wherein R8 is lower alkyl and R9 is hydrogen can be produced by the following method. 
wherein R8a is lower alkyl, and the other symbols are as defined above.
The acid catalyst used for Friedel-Crafts reaction of compound (XXVII) is, for example, aluminum chloride, aluminum bromide, titanium chloride, sulfuric acid, zinc chloride, iron chloride or hydrogen fluoride, phosphoric acid.
The solvent to be used for the Friedel-Crafts reaction may be, for example, tetrahydrofuran, dioxane, diethyl ether, dichloromethane, dichloroethane, chloroform, ethylene glycol dimethyl ether, acetonitrile, nitromethane, carbon disulfide or a mixture thereof. Where necessary, the solvent may not be used.
The reaction temperature of the Friedel-Crafts reaction is generally from xe2x88x9220 C. to 100xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of reduction of the Friedel-Crafts reaction is generally from 30 minutes to 24 hours, and a time longer or shorter than this range can be employed as necessary.
The reducing agent to be used for reduction of the carbonyl group in compound (XXIX) may be, for example, a metallic reducing reagent such as aluminum lithium hydride, sodium borohydride, lithium borohydride and the like, or diborane.
The solvent to be used for reduction of the carbonyl group may be, for example, water, tetrahydrofuran, dioxane, diethyl ether, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, ethylene glycol dimethyl ether, a mixture thereof, and the like.
The reaction temperature of reduction of the carbonyl group is generally from xe2x88x9220xc2x0 C. to 80xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of reduction of the carbonyl group is generally from 30 minutes to 10 hours, and a time longer or shorter than this range can be employed as necessary.
The obtained compound (XXX) is converted to a group Q by a method known in the field of organic synthetic chemistry to produce compound (XIV-a).
The group Q of compound (XIV-a) is converted to a group Lv as necessary by a method known in the field of organic synthetic chemistry and condensed with compound (III) in the same manner as in Method A. Where necessary, the protecting group(s) is/are removed to produce compound (I) wherein R9 is hydrogen, namely, compound (I-9) 
wherein each symbol is as defined above.
After each reaction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), the synthetic intermediate in each step and the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method N
Compound (II) wherein R8 and R9 are both hydrogen and Lv is particularly halogen can be produced by the following method. 
wherein each symbol is as defined above.
The reagent to be used for halomethylation of compound (XXVII) is exemplified by formaldehyde and hydrogen chloride, formaldehyde and hydrogen bromide, formaldehyde and hydrogen iodide, chloromethyl methyl ether, bis(chloromethyl) ether, methoxyacetyl chloride and 1-chloro-4-(chloromethoxy)butane.
The catalyst to be used for halomethylation is, for example, zinc chloride, aluminum chloride, aluminum bromide, titanium chloride or iron chloride.
The solvent to be used for halomethylation may be, for example, tetrahydrofuran, dioxane, diethyl ether, dichloromethane, dichloroethane, chloroform, ethylene glycol dimethyl ether, acetonitrile, nitromethane, carbon disulfide or a mixture thereof.
The reaction temperature of halomethylation is generally from xe2x88x9220xc2x0 C. to 100xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of halomethylation is generally from 30 minutes to 24 hours, and a time longer or shorter than this range can be employed as necessary.
After halomethylation under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), compound (II-b) can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Moreover, compound (II-b) and compound (III) are condensed in the same manner as in Method A to produce compound (I-8).
Method O
Compound (XXVI) can be also produced by the following method. 
wherein each symbol is as defined above.
The Lewis acid to be used for the reaction with dichloromethyl methyl ether may be, for example, aluminum chloride, titanium tetrachloride, tin tetrachloride, antimony(v)chloride, iron(III) chloride, boron trifluoride, bismuth(III) chloride, zinc chloride, mercury(II) chloride and the like.
The organic solvent to be used for the reaction with dichloromethyl methyl ether may be, for example, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, methylene chloride, chloroform, dichloroethane, acetonitrile, nitromethane, carbon disulfide and the like. Where necessary, a solvent may not be used.
The temperature of reaction with dichloromethyl methyl ether is generally from xe2x88x9250xc2x0 C. to 50xc2x0 C., and a temperature above or under this range can be employed as necessary.
The time of reaction with dichloromethyl methyl ether is generally from 30 minutes to 24 hours, and a time longer or shorter than this range can be employed as necessary.
The reducing agent to be used for reduction of the formyl group in compound (XXXI) may be, for example, a metallic reducing reagent such as aluminum lithium hydride, sodium borohydride, lithium borohydride and the like, or diborane.
The solvent to be used for reduction of the formyl group may be, for example, water, tetrahydrofuran, dioxane, diethyl ether, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, ethylene glycol dimethyl ether, a mixture thereof, and the like.
The reaction temperature of reduction of the formyl group is generally from xe2x88x9220xc2x0 C. to 80xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of reduction of the formyl group is generally from 30 minutes to 10 hours, and a time longer or shorter than this range can be employed as necessary.
The compound (XXVI) can be produced using a haloform reaction as the key reaction.
The acylation of compound (XXVII) with acetyl chloride is performed under the same reaction conditions as in Method M.
The reagent to be used for the haloform reaction of compound (XXIXa) may be, for example, base (e.g., sodium hydroxide, potassium hydroxide and the like), and a halogenating agent (e.g., bromine, chlorine, sodium (potassium) hypochlorite, sodium (potassium) hypobromite and the like).
The solvent to be used for haloform reaction may be, for example, water, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, tetrahydrofuran, dioxane, a mixture thereof, and the like.
The temperature of haloform reaction is generally from xe2x88x9220xc2x0 C. to 100xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of haloform reaction is generally from 30 minutes to 24 hours, and a time longer or shorter than this range can be employed as necessary.
Conversion of compound (XXVa) via compound (XXVb) to compound (XXVI) is performed under the reaction conditions described for Method L.
The compound (XXVa) can be also produced by directly from compound (XXVII) by Friedel-Crafts reaction using oxalyl chloride. The Friedel-Crafts reaction using oxalyl chloride is performed under the reaction conditions described for Method M.
After each reaction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), the synthetic intermediate in each step and the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
The compound (XXXI) can be also produced from compound (XXVII) using known Friedel-Crafts type reaction widely used in the field of organic synthetic chemistry, such as Gattermann-Koch method, Gattermann method, Vilsmeier method, Duff method.
Method P
The compound (XIV), compound (II-a), compound (XV) can be converted to compound (XX) by introducing an amino group described in, for example, Method D, Method E and Method F.
Method Q
Compound (I-1) and compound (XII) wherein R8 and R9 are both hydrogen can be also produced by the following method. 
wherein Ya is single bond or alkyl having one less carbon atoms than Y defined above, A is hydroxy or amino, and the other symbols are as defined above.
For condensation of compound (XXXII) and compound (III), for example, 1) acid chloride method and 2) mixed acid anhydride method widely used in the field of organic synthetic chemistry are particularly effective.
The reagent used for the acid chloride method may be, for example, thionyl chloride and oxazolyl chloride.
The solvent to be used for acid chloride method may be, for example, tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether, benzene, dichloromethane, dichloroethane, chloroform, toluene, xylene and hexane.
The reaction temperature of acid chloride method is generally from 0xc2x0 C. to 80xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of acid chloride method is generally from 30 minutes to 2 days, and a time longer or shorter than this range can be employed as necessary.
The reagent used for the mixed acid anhydride method may be, for example, methyl chlorocarbonate, ethyl chlorocarbonate, isopropyl chlorocarbonate, isobutyl chlorocarbonate or phenyl chlorocarbonate.
The base to be used for mixed acid anhydride method may be, for example, triethylamine, diisopropylethylamine, potassium carbonate, potassium hydrogencarbonate, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, sodium methoxide or sodium ethoxide.
The solvent to be used for acid anhydride method may be, for example, tetrahydrofuran, dioxane, acetone, diethyl ether, ethylene glycol dimethyl ether, benzene, dichloromethane, dichloroethane, chloroform, toluene, xylene or hexane.
The reaction temperature of mixed acid anhydride method is generally from xe2x88x9280xc2x0 C. to 20xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of acid anhydride method is generally from 30 minutes to 2 days, and a time longer or shorter than this range can be employed as necessary.
The reducing agent to be used for compound (XXXIII) may be, for example, a metallic reducing reagent (e.g., aluminum lithium hydide, sodium borohydride, lithium borohydride and the like), or diborane.
The solvent to be used for reduction may be, for example, water, tetrahydrofuran, dioxane, diethyl ether, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, ethylene glycol dimethyl ether, a mixture thereof, and the like.
The reaction temperature of reduction is generally from xe2x88x9220xc2x0 C. to 80xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of reduction is generally from 30 minutes to 10 hours, and a time longer or shorter than this range can be employed as necessary.
After each reaction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), the synthetic intermediate in each step and the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method R
Compound (I-1) can be also produced by the following method. 
wherein each symbol is as defined above.
The compound (XXXV) and compound (III) are condensed under the same reaction conditions as in Method A.
The group Q of compound (XXXVI) is converted to a leaving group Lv as necessary by a method known in the field of organic synthetic chemistry and then subjected to cyanation.
The reagent to be used for cyanation may be, for example, sodium cyanide or potassium cyanide.
The solvent to be used for cyanation may be, for example, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide or a mixture thereof.
The reaction temperature of cyanation is generally from 0xc2x0 C. to 150xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of cyanation is generally from 30 minutes to 2 days, and a time longer or shorter than this range can be employed as necessary.
The reducing agent to be used for reduction of the cyano group in compound (XXXVII) may be, for example, a metallic reducing reagent such as aluminum lithium hydide, sodium borohydride and lithium borohydride, or diborane.
The solvent to be used for cyanation may be, for example, tetrahydrofuran, dioxane, diethyl ether, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, ethylene glycoldimethyl ether, a mixture thereof, and the like.
The reaction temperature of reduction of the cyano group is generally from xe2x88x9220xc2x0 C. to 80xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of reduction of the cyano group is generally from 30 minutes to 10 hours, and a time longer or shorter than this range can be employed as necessary.
After each reaction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), the synthetic intermediate in each step and the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method S
Compound (XXXVII) can be also produced by the following method. 
wherein each symbol is as defined above.
In this method, the conditions of cyanation are the same as in Method R and those of condensation are the same as in Method A.
After cyanation and condensation under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), the synthetic intermediate in each step and the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method T
Compound (XXV) wherein R1 is hydrogen and R2 is nitro can be produced by the following method. 
wherein each symbol is as defined above.
By this nitration, compound (XXV-b) is mainly produced.
The reagent to be used for nitration may be, for example, nitric acid, mixed acid, acetyl nitrate, dinitrogen pentaoxide or nitronium salt.
The solvent to be used for nitration may be, for example, water, acetic acid, acetic anhydride, con. sulfuric acid, chloroform, dichloromethane, carbon disulfide, dichloroethane or a mixture thereof, or the solvent may not be used.
The reaction temperature of nitration is generally from xe2x88x9220xc2x0 C. to 80xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of nitration is generally from 30 minutes to 10 hours, and a time longer or shorter than this range can be employed as necessary.
After nitration under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), compound (XXV-b), compound (XXV-c) can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Further, compound (XXV-b) and compound (XXV-c) are reacted in the same manner as in Method L to produce compound (I-8a) 
wherein each symbol is as defined above.
Method U
Compound (I-8) wherein R1 is hydrogen and R2 is amino can be produced by the following method. 
wherein each symbol is as defined above.
The reducing agent to be used for reduction of the nitro group may be, for example, a metallic reducing reagent (e.g., sodium borohydride, lithium borohydride, aluminum lithium hydide and the like), reduction using metal (e.g., iron, zinc, tin and the like), and catalytic reduction using transition metal (e.g., palladium-carbon, platinum oxide, Raney-nickel, rhodium, ruthenium and the like). When catalytic reduction is applied, ammonium formate, sodium dihydrogenphosphate, hydrazine and the like can be used as the hydrogen source.
The solvent to be used for reduction of the nitro group may be, for example, water, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, dioxane, acetone, ethyl acetate, acetic acid, benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide or a mixture thereof.
The reaction temperature of reduction of nitro is generally from xe2x88x9220xc2x0 C. to 150xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of reduction of nitro is generally from 30 minutes to 2 days, and a time longer or shorter than this range can be employed as necessary.
After reduction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), compound (I-8b) can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
In compound (I-8b), when R6 and R7 are not hydrogen and R3, R4 and R5 are not amino, the functional group (hydroxy and the like) are protected as necessary, and the compound is subjected to the reactions as described in Method B1 to Method B8 to produce a compound wherein the amino group on the corresponding phenylene ring has been alkylated and/or acylated.
Method V
Compound (I-8) wherein R1 is hydrogen, R2 is hydrogen, halogen (e.g., fluorine, chlorine, bromine or iodine), hydroxy or cyano can be produced by the following method. 
wherein Rg is hydrogen, halogen (e.g., fluorine, chlorine, bromine or iodine), hydroxy or cyano, and the other symbols are as defined above.
As the Sandmeyer type reaction, Sandmeyer reaction, Gattermann reaction, Schiemann reaction and the like are exemplified. The Sandmeyer type reaction comprises processes of diazotization of amine and nucleophilic substitution of the resulting diazonium salt using various nucleophiles.
For diazotization, an aqueous sodium nitrite solution, nitrous acid and organic nitrite ester (e.g., isopentyl nitrite) are generally used.
The solvent to be used for diazotization may be, for example, water, hydrochloric acid, hydrobromic acid, nitric acid, dilute sulfuric acid, benzene, toluene or a mixture thereof.
The reaction temperature of diazotization is generally from xe2x88x9220xc2x0 C. to 100xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of diazotization is generally from 10 minutes to 5 hours, and a time longer or shorter than this range can be employed as necessary.
The reagent to be used for nucleophilic substitution may be, for example, hypophosphorous acid, fluoroboric acid, hydrochloric acidxe2x80x94copper(I) chloride, hydrochloric acidxe2x80x94Gattermann copper, hydrobromic acidxe2x80x94copper(I) bromide, hydrobromic acidxe2x80x94Gattermann copper, iodine, potassium iodide, sodium iodide, trimethylsilyl iodide, water, copper(I) cyanide, sodium cyanide, potassium cyanide and the like.
The solvent to be used for nucleophilic substitution may be, for example, water, hydrochloric acid, hydrobromic acid, nitric acid, dilute sulfuric acid, benzene, toluene, chloroform, dichloromethane, acetonitrile or a mixture thereof.
The reaction temperature of nucleophilic substitution is generally from xe2x88x9220xc2x0 C. to 100xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of nucleophilic substitution is generally from 30 minutes to 5 hours, and a time longer or shorter than this range can be employed as necessary.
After nucleophilic substitution under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), compound (I-8c) can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method W
Compound (XXV) wherein R1 is hydrogen and R2 is amino can be produced by the following method. 
wherein each symbol is as defined above.
The reaction conditions of reduction of nitro are the same as in Method U.
After reduction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), compound (XXV-d) can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Further, the amino group of compound (XXV-d) is protected and reacted in the same manner as in Method L to produce compound (I-8b).
Method X
Compound (XXV) wherein R1 is hydrogen, R2 is hydrogen, halogen (e.g., fluorine, chlorine, bromine or iodine), hydroxy or cyano can be produced by the following method. 
wherein each symbol is as defined above.
The reaction conditions of Sandmeyer type reaction are the same as in Method V.
After Sandmeyer type reaction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), compound (XXV-e) can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Further, compound (XXV-e) is reacted in the same manner as in Method L to produce compound (I-8c).
Method Y
Compound (XXIX) wherein R1 is hydrogen and R2 is nitro can be produced by the following method. 
wherein each symbol is as defined above.
The reaction conditions of nitration are the same as in Method T.
After nitration under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), compound (XXIX-b) can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Further, compound (XXIX-b) is reacted in the same manner as in Method M, Method G or Method I to produce compound (I-9a) 
wherein each symbol is as defined above.
Method Z
Compound (I-9) wherein R1 is hydrogen and R2 is amino can be produced by the following method. 
wherein each symbol is as defined above.
The reaction conditions of reduction are the same as in Method U.
After reduction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), compound (I-9b) can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
In compound (I-9b) , when R6 and R7 are not hydrogen and R3, R4 and R5 are not amino, the functional group (hydroxy and the like) are protected as necessary, and the compound is subjected to the reactions as described in Method B1 to Method B8 to produce a compound wherein the amino group on the corresponding phenylene ring has been alkylated and/or acylated.
Method AA
Compound (I-9) wherein R1 is hydrogen and R2 is hydrogen, halogen (e.g., fluorine, chlorine, bromine or iodine), hydroxy or cyano can be produced by the following method. 
wherein each symbol is as defined above.
The reaction conditions of Sandmeyer type reaction are the same as in Method V.
After Sandmeyer type reaction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), compound (I-9c) can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method BB
The compound (X) can be produced by subjecting compound (XII) to Mitsunobu reaction in the same manner as in Method F using hydrogen azide.
The reaction conditions (reagent, solvent, reaction temperature, reaction time) of Mitsunobu reaction are the same as in Method F.
After Mitsunobu reaction under the above-mentioned reaction conditions, the protecting group(s) is/are removed as necessary, and compound (X) can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method CC
Compound (I) wherein Y is methylene and R8 and R9 are both hydrogen can be produced by the following method. 
wherein Hal is halogen such as chlorine, bromine, iodine and the like, and the other symbols are as defined above.
The halogenizing agent to be used for the halogenation of compound (XL) may be, for example, halogen (e.g., chlorine, bromine, iodine and the like), N-bromosuccinimide, N-chlorosuccinimide, sulfuryl chloride, hypohalite tert-butyl and the like. For acceleration of the reaction, a radical initiator such as dibenzoyl peroxide, azobisisobutyronitrile and the like can be used. In addition, the reaction may be carried out under heat or light for acceleration of the reaction.
The solvent to be used for halogenation is preferably carbon tetrachloride.
The reaction temperature of halogenization is generally from 0xc2x0 C. to 100xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of halogenization is generally 1 to 12 hours, and a time longer or shorter than this range can be employed as necessary.
The reducing agent to be used for reduction of compound (XLI) may be, for example, those used in catalytic reduction such as diisobutylaluminum hydride, sodium borohydridexe2x80x94cobalt (II) chloride, aluminum lithium hydridexe2x80x94aluminum chloride, lithium trimethoxyaluminum hydride, boranexe2x80x94methyl sulfide and transition metal (e.g., palladium-carbon, platinum oxide, Raney-nickel, rhodium, ruthenium and the like).
The solvent to be used for reduction may be, for example, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, dioxane, ethyl acetate, benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide and the like.
The reaction temperature of reduction is generally from xe2x88x9220xc2x0 C. to 80xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of reduction is generally from 30 minutes to 24 hours, and a time longer or shorter than this range can be employed as necessary.
The compound resulting from reduction is alkylated, aralkylated, acylated or protected by a protecting group as necessary by a method known in the field of organic synthetic chemistry to live compound (II-c).
Further, compound (II-c) and compound (III) are condensed in the same manner as in Method A to produce compound (I-10).
After each reaction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), the synthetic intermediate in each step and the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method DD
Compound (III) can be produced by the following method. 
wherein Ac is acetyl, and the other symbols are as defined above.
The compound (XLII) and 1-acetylpiperazine are condensed under the same reaction conditions as in Method K.
The reagent used for hydrolysis of compound (III-a) may be, for example, hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide and the like.
The solvent to be used for hydrolysis may be, for example, water, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, acetone, tetrahydrofuran, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide or a mixture thereof.
The reaction temperature of hydrolysis is generally from xe2x88x9220xc2x0 C. to 100xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of hydrolysis is generally from 30 minutes to 2 days, and a time longer or shorter than this range can be employed as necessary.
The solvent to be used for condensation to directly obtain compound (III) from compound (XLII) and piperazine may be, for example, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether, benzene, dichloromethane, dichloroethane, chloroform, toluene, xylene, hexane, dimethylformamide, dimethyl sulfoxide, acetonitrile or a mixture thereof, or the solvent may not be used.
The reaction temperature of condensation is generally from 0xc2x0 C. to 150xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of condensation is generally from 30 minutes to 2 days, and a time longer or shorter than this range can be employed as necessary.
After each reaction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), the synthetic intermediate in each step and the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method EE
Compound (III) can be also produced by the following method. 
wherein each symbol is as defined above.
The reducing agent to be used for reduction of the nitro group in compound (XLIII) may be, for example, a metallic reducing reagent such as sodium borohydride, lithium borohydride, aluminum lithium hydide and the like, reduction with metal (e.g., iron, zinc, tin and the like), and catalytic reduction using transition metal (e.g., palladium-carbon, platinum oxide, Raney nickel, rhodium, ruthenium and the like). When catalytic reduction is applied, ammonium formate, sodium dihydrogenphosphate, hydrazine and the like can be used as the hydrogen source.
The solvent to be used for reduction of the nitro group may be, for example, water, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, dioxane, acetone, ethyl acetate, acetic acid, benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide or a mixture thereof.
The reaction temperature of reduction of nitro is generally from xe2x88x9220xc2x0 C. to 80xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of reduction is generally 1 to 24 hours, and a time longer or shorter than this range can be employed as necessary.
The compound (XIX) and compound (XVII-a) are condensed under the same reaction conditions as in Method A to produce compound (III).
After each reaction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), the synthetic intermediate in each step and the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method FF
The compound (I) wherein Y is a group of the formula 
wherein each symbol is as defined above,and R9 is hydrogen, can be produced by the following method. 
wherein G is a hydroxyl group or lower alkoxy, and the other symbols are as defined above.
The organic solvent to be used for addition reaction of compound (XLIV) may be, for example, tetrahydrofuran, diethyl ether, ethylene glycoldimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane and the like.
The reaction temperature of addition is generally from xe2x88x9220xc2x0 C. to 100xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of addition is generally from 30 minutes to 2 days, and a time longer or shorter than this range can be employed as necessary.
The reducing agent to be used for reduction of compound (XLV) may be, for example, sodium borohydride, lithium borohydride, aluminum lithium hydride, diisobutylaluminum hydride, lithium trimethoxyaluminum hydride, lithium tri-tert-butoxyaluminum hydride, diborane and the like.
The organic solvent to be used for reduction may be, for example, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, acetone and methyl ethyl ketone.
The reaction temperature of reduction is generally from xe2x88x92100xc2x0 C. to 80xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of reduction is generally from 30 minutes to 10 hours, and a time longer or shorter than this range can be employed as necessary.
The organic solvent to be used for Ritter reaction of compound (XLVI) may be, for example, hydrogen cyanide, acetonitrile, benzonitrile and the like.
The organic solvent to be used for Ritter reaction may be, for example, acetic acid, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane and the like.
The acid catalyst to be used for Ritter reaction may be, for example, strong acid such as sulfuric acid, trifluoroacetic acid and the like.
The reaction temperature of Ritter reaction is generally from xe2x88x9220xc2x0 C. to 80xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of Ritter reaction is generally from 30 minutes to 24 hours, and a time longer or shorter than this range can be employed as necessary.
The compound obtained by Ritter reaction is hydrolyzed, alkylated, aralkylated, acylated or protected by a protecting group as necessary by a method known in the field of organic synthetic chemistry to produce compound (XLVII).
The compound (XLVII) and compound (III) are condensed under the same reaction conditions as in Method A to produce compound (I-11).
After each reaction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), the synthetic intermediate in each step and the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method GG
The compound (I) wherein Y is a group of the formula 
wherein each symbol is as defined above, and R9 is hydrogen, can be produced by the following method. 
wherein each symbol is as defined above.
The addition reaction of compound (XLV) and Ritter reaction of compound (XLVIII) can be carried out under the same reaction conditions as in Method FF.
The compound (XLIX) and compound (III) are condensed under the same reaction conditions as in Method A.
After each reaction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), the synthetic intermediate in each step and the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method HH
Compound (XXIX) and compound (XXX) can be also produced by the following method. 
wherein each symbol is as defined above.
The azidating agent to be used for azidation of compound (L) is exemplified by metal azide (e.g., sodium azide, lithium azide and the like) and the like.
The reaction temperature of azidation is generally from 0xc2x0 C. to 100xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of azidation is generally 1 to 24 hours, and a time longer or shorter than this range can be employed as necessary.
The reducing agent to be used for reduction of compound (LI) may be, for example, a metallic reducing reagent such as sodium borohydride, lithium borohydride, aluminum lithium hydride and the like, triphenylphosphine, and catalytic reduction using transition metal (Lindlar catalyst (palladium, calcium carbonate), palladium-carbon, Raney nickel, platinum oxide, rhodium, ruthenium and the like). For the selective reduction of the azide group alone of compound (LI), catalytic reduction using triphenylphosphine or transition metal is particularly effective.
The organic solvent to be used for reduction may be, for example, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, dioxane, acetone, ethyl acetate, acetic acid, benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide and the like.
The reaction temperature of reduction is generally from xe2x88x9220xc2x0 C. to 80xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of reduction is generally 1 to 24 hours, and a time longer or shorter than this range can be employed as necessary.
The compound obtained by reduction is alkylated, aralkylated, acylated or protected by a protecting group as necessary by a method known in the field of organic synthetic chemistry to produce compound (XXIX).
After reaction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), the synthetic intermediate in each step and the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method II
Compound (I) wherein Y is methylene and R8 and R9 are the same or different and each is lower alkyl can be produced by the following method. 
wherein R9a is lower alkyl, and the other symbols are as defined above.
The base to be used for condensation of compound (LII) may be, for example, sodium methoxide, sodium ethoxide, sodium hydride, potassium hydride, lithium diisopropylamide, lithium hexamethyldisilazane, diisopropylethylamine, 1,8-diazabicyclo[4.3.0]undeca-5-ene, sodium amide and the like.
The organic solvent to be used for condensation may be, for example, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane, acetonitrile and the like.
The reaction temperature of condensation is generally from xe2x88x9220xc2x0 C. to 150xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of condensation is generally from 30 minutes to 2 days, and a time longer or shorter than this range can be employed as necessary.
The base to be used for hydrolysis of compound (LIII) may be, for example, acid such as hydrochloric acid, sulfuric acid, formic acid, acetic acid and the like, or alkali such as sodium hydroxide, potassium hydroxide and the like.
The solvent to be used for hydrolysis may be, for example, water, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, ethylene glycol, diethylene glycol, a mixture thereof, and the like.
The reaction temperature of hydrolysis is generally from xe2x88x9220xc2x0 C. to 150xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of hydrolysis is generally from 30 minutes to 2 days, and a time longer or shorter than this range can be employed as necessary.
After halogenation of compound (LIV), the compound is subjected to azidation to produce compound (LIX). The halogenation of compound (LIV) can be performed under the same reaction conditions as in Method CC. The obtained halogenated compound is subjected to azidation under the same reaction conditions as in Method HH.
The compound (LV) is reduced under the same reaction conditions as in Method HH.
The base to be used for curtius rearrangement of compound (LVI) may be, for example, Hxc3xcnig base such as triethylamine, diisopropylethylamine and the like. When the substrate of this reaction, carboxylic acid, is a salt, a base is not necessary.
The activator to be used for Curtius rearrangement is exemplified by methyl chlorocarbonate, ethyl chlorocarbonate, isopropyl chlorocarbonate, isobutyl chlorocarbonate, phenyl chlorocarbonate and the like.
The azidating agent to be used for Curtius rearrangement is exemplified by sodium azide, diphenylphosphoryl azide (when this reagent is used, base or activator is not necessary) and the like.
The solvent to be used for Curtius rearrangement may be, for example, aprotic solvent in the former half of the reaction, such as tetrahydrofuran, acetone, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, dioxane, methylene chloride, chloroform, dichloroethane, acetonitrile and the like, and in the latter half of the reaction, for example, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane, acetonitrile or benzyl alcohol is used.
The reaction temperature of Curtius rearrangement is generally from xe2x88x9220xc2x0 C. to 150xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of Curtius rearrangement is generally from 30 minutes to 10 hours, and a time longer or shorter than this range can be employed as necessary.
The carbamic acid compound obtained by Curtius rearrangement is treated with benzyl alcohol and subjected to catalytic reduction to produce compound (LVII). When carbamic acid compound is treated with an alcohol solution of acid (e.g., hydrochloric acid, sulfuric acid and the like) or alkali (e.g., sodium hydroxide, potassium hydroxide and the like), or trimethylsilyl iodide, compound (LVII) can be produced.
The compound (LVII) and compound (XXI) are condensed under the same reaction conditions as in Method J.
After each reaction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), the synthetic intermediate in each step and the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method JJ
Compound (XVIII) can be produced by the following method. 
wherein each symbol is as defined above.
The compound (XX) and compound (XXIIa) are condensed under the same reaction conditions as in Method J.
The compound (XX) and compound (XXIIc) are condensed under the same reaction conditions as in Method J. The compound (XXb) is reduced under the same reaction conditions as in Method J.
After each reaction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), the synthetic intermediate in each step and the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method KK
Compound (I) wherein m=n=0, R12 and R13 in combination form ethylene and R8 and R9 are both hydrogen can be produced by the following method. 
wherein each symbol is as defined above.
The compound (LXI) is halomethylated under the same reaction conditions as in Method N.
The compound (LXII) and compound (III) are condensed under the same reaction conditions as in Method A.
The compound (LXIII) is subjected to Curtius rearrangement under the same reaction conditions as in Method II. The carbamic acid compound obtained by Curtius rearrangement is reacted with a Grignard reagent to produce compound (I-13) wherein R6 or R7 is acylated. The amine compound obtained by Curtius rearrangement is alkylated, aralkylated or acylated by a method known in the field of organic synthetic chemistry to produce compound (I-13).
After each reaction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), the synthetic intermediate in each step and the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method LL
Compound (I) wherein m=n=0, R12 and R13 in combination form ethylene and R9 is hydrogen can be produced by the following method. 
wherein each symbol is as defined above.
The compound (LXIV) is subjected to Curtius rearrangement under the same reaction conditions as in Method KK.
The Friedel-Crafts reaction of compound (LXV) and reduction of compound (LXVI) can be carried our under the same reaction conditions as in Method M. The hydroxyl group of compound (LXVII) is converted to a leaving group Lv by a method known in the field of organic synthetic chemistry to give compound (LXVIII), which is then condensed with compound (III) in the same manner as in Method A to produce compound (I-14).
After each reaction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), the synthetic intermediate in each step and the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method MM
Compound (XXIV) wherein Lv1 is chlorine or bromine can be produced by the following method. 
wherein each symbol is as defined above.
The compound (XIX) is subjected to Sandmeyer type reaction under the same reaction conditions as in Method V.
After Sandmeyer type reaction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), compound (XXIV) can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method NN
Compound (XXIV) wherein Lv1 is chlorine can be produced by the following method. 
wherein each symbol is as defined above.
This method is particularly effective for converting the hydroxyl group of hetero ring derivative, such as 2-hydroxypyrimidine, 2-hydroxypyridine and the like, to chloride.
The reagent to be used for chlorination of compound (LXIX) may be, for example, phosphorous oxychloride.
The solvent to be used for chlorination may be, for example, dichloromethane, dichloroethane, chloroform, carbon tetrachloride or a mixture thereof, or the reaction proceeds without solvent.
The reaction temperature of chlorination is generally from 0xc2x0 C. to 150xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of chlorination is generally from 30 minutes to 2 days, and a time longer or shorter than this range can be employed as necessary.
After chlorination under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), compound (XXIV) can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
Method OO
Compound (XXVII) wherein m=n=0 at Y can be produced by the following method. 
wherein each symbol is as defined above.
The reagent to be used for halogenation of compound (LXX) may be, for example, N-bromosuccimide and N-chlorosuccimide.
For the halogenation, a radical initiator such as 2,2xe2x80x2-azobisisobutyronitrile (AIBN), benzoyl peroxide and the like can be used as necessary.
The solvent to be used for halogenation may be, for example, carbon tetrachloride, chloroform, dichloromethane or benzene.
The reaction temperature of halogenation is generally from 0xc2x0 C. to 150xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of halogenation is generally from 30 minutes to 2 days, and a time longer or shorter than this range can be employed as necessary.
The reagent to be used for ammonolysis of compound (LXXI) may be, for example, liquid ammonia.
The solvent to be used for ammonolysis may be, for example, water, methanol, ethanol, 1-propanol, tetrahydrofuran, dioxane or a mixture thereof.
The reaction temperature of ammonolysis is generally from 0xc2x0 C. to 150xc2x0 C., and a temperature above or under this range can be employed as necessary.
The reaction time of ammonolysis is generally from 30 minutes to 2 days, and a time longer or shorter than this range can be employed as necessary.
The compound (LXXII) can be converted to compound (XXVII) according to Methods B1 to B8.
After each reaction under the above-mentioned reaction conditions and, where necessary, removal of protecting group(s), the synthetic intermediate in each step and the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography, and a method using an ion exchange resin.
The compound (I) of the present invention can be treated with an acid (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, benzoic acid, citric acid, succinic acid, tartaric acid, malic acid, mandelic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid and the like), as necessary, in a suitable solvent (e.g., water, methanol, ethanol, diethyl ether, tetrahydrofuran, dioxane and the like) to convert to a pharmaceutically acceptable salt. The compound (I) of the present invention can be converted to a quaternary ammonium salt by treating with lower alkyl halide (e.g., methyl iodide, methyl bromide, ethyl iodide, ethyl bromide and the like) in the presence of a base. When the obtained crystals of the compound of the present invention are anhydride, the compound of the present invention is treated with water, a water-containing solvent or a different solvent to give a hydrate (e.g., monohydrate, 1/2 hydrate, 1/4 hydrate, 1/5 hydrate, dihydrate, 3/2 hydrate, 3/4 hydrate and the like) or solvate.
The compound of the present invention thus obtained can be isolated and purified by a conventional method such as recrystallization, column chromatography and the like. When the resulting product is a racemate, for example, a desired optically active compound can be resolved by fractional recrystallization of a salt with an optically active acid or by passing the racemate through a column packed with an optically active carrier. Individual diastereomers can be separated by fractional crystallization, chromatography and the like. These can be also obtained by using an optically active starting compound.
The compound of the present invention has a TNF-xcex1 production inhibitory effect and/or IL-10 production promoting effect, and is useful for the prophylaxis and treatment of various diseases caused by abnormal TNF-xcex1 production, diseases treatable with IL-10, such as chronic inflammatory disease, acute inflammatory disease, inflammatory disease due to infection, autoimmune diseases, allergic diseases, and other TNF-xcex1 mediated diseases.
The chronic inflammatory diseases include osteoarthritis, psoriatic arthritis, inflammatory dermal disease (psoriasis, eczematoid dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, vascular edema, angiitis, erythema, dermal eosinophilia, acne, alopecia areata, eosinophilic fasciitis, atherosclerosis and the like), inflammatory bowel disease (ulcerative colitis, Crohn""s disease and the like) and the like.
The acute inflammatory diseases include contact dermatitis, adult respiratory distress syndrome (ARDS), sepsis (inclusive of organ disorders etc. caused by sepsis), septic shock, and the like.
The inflammatory diseases due to infection include endotoxin shock, acquired immunodeficiency syndrome (AIDS), meningitis, cachexia, viral hepatitis, fulminant hepatitis, other inflammatory responses due to infection with bacteria, virus, mycoplasma and the like (inclusive of fever, pain, organ disorders caused by influenzal or non-influenzal cold and the like) and the like.
The autoimmune diseases include rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, glomerular nephritis (nephrotic syndrome (idiopathic nephrotic syndrome, minimal-change nephropathy and the like) and the like), multiple sclerosis, polychondritis, scleroderma, dermatomyositis, wegener""s granulomatosis, active chronic hepatitis I, primary biliary cirrhosis, myasthenia gravis, idiopathic sprue, Graves"" disease, sarcoidosis, Reiter""s syndrome, juvenile diabetes (type I diabetes mellitus), autoimmune ophthalmic disease (endocrine ophthalmopathy, uveitis, keratitis (keratoconjunctivitis sicca, vernal keratoconjunctivitis and the like) and the like), Behqet""s disease, autoimmune hemopathy (hemolytic anemia, aplastic anemia, idiopathic thrombocytopenia and the like), various malignant tumors (adenocarcinoma and the like), matastatic carcinoma and the like.
The allergic diseases include atopic dermatitis, asthmatic diseases (bronchial asthma, infantile asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, late-onset asthma, bronchial hypersensitivity, bronchitis and the like), allergic rhinitis, allergic conjunctivitis and the like.
Other TNF-xcex1 mediated diseases include resistant responses in organ or tissue transplantation (e.g., allograft or xenograft of heart, kidney, liver, lung, bone marrow, cornea, pancreas, pancreatic cell, small intestine, duodenum, limbs, muscle, nerve, fatty marrow, skin and the like) in mammals such as human, dog, cat, cow, horse, swine, monkey, mice and the like, i.e., rejection and graft versus host disease (GvHD), osteoporosis, cancer cachexia, thermal burn, trauma, scald, inflammatory response (inclusive of shock)and the like against plant and animal components (inclusive of snake venom and the like) and administration of drug and the like, myocardial infarction, chronic heart failure, congestive heart failure, ischemia-reperfusion injury, Kawasaki disease, pneumonia, malaria, meningitis, peritonitis, fibroid lung and disseminated intravascular coagulation (DIC). In addition to these, the inventive compound is useful for the prophylaxis and treatment of hepatopathy.
The compound of the present invention is characteristically void of effect on the central nervous system, because it has no or extremely weak affinity for the receptors distributed in the central nervous system. Moreover, the compound of the present invention having a TNF-xcex1 production inhibitory effect and an IL-10 production promoting effect is expected to show superior prophylactic and therapeutic effects on the above-mentioned diseases, particularly chronic diseases such as rheumatoid arthritis, chronic inflammatory diseases and the like, by the synergistic action of these two effects. In the present invention, a compound having these two effects is preferable.
When the compound (I) of the present invention is used as a TNF-xcex1 production inhibitor and/or an IL-10 production promoter, it is prepared into a typical pharmaceutical preparation. For example, the compound of the present invention (I) is prepared into a dosage form suitable for oral or parenteral administration upon admixing with a pharmaceutically acceptable carrier (excipient, binder, disintegrant, corrigent, flavor, emulsifier, diluent, solubilizer and the like) to give a pharmaceutical composition or preparation, such as tablet, pill, powder, granule, capsule, troche, syrup, liquid, emulsion, suspension, injection (liquid, suspension and the like), suppository, inhalent, transdermal absorber, eye drop, nose drop, eye ointment and the like.
When a solid preparation is produced, an additive is used, such as sucrose, lactose, cellulose sugar, D-mannitol, maltitol, dextran, starches, agar, arginates, chitins, chitosans, pectins, tragacanth, acacia, gelatins, collagens, casein, albumin, calcium phosphate, sorbitol, glycine, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, glycerol, polyethylene glycol, sodium hydrogencarbonate, magnesium stearate, talc and the like. The tablets can be made into those having typical tablet film, as necessary, such as sugar-coated tablet, enteric coated tablet, film coating tablet, or two-layer tablet, or multi-laye tablet.
When a semi-solid preparation is produced, plant and animal fats and oils (olive oil, corn oil, castor oil and the like), mineral oils (petrolatum, white petrolatum, solid paraffin and the like), wax (jojoba oil, carnauba wax, bee wax and the like), partially synthesized or completely synthesized glycerol fatty acid ester (lauric acid, myristic acid, palmitic acid and the like), and the like are used. Commercially available products of these are, for example, Witepsol (manufactured by Dynamitnovel Ltd.), pharmasol (manufactured by Japan Oil and Fat Co. Ltd.) and the like.
When a liquid preparation is produced, an additive is used, such as sodium chloride, glucose, sorbitol, glycerol, olive oil, propylene glycol, ethyl alcohol and the like. In particular, when an injection is prepared, sterile aqueous solution, such as physiological saline, isotonic liquid and oily liquid (e.g., sesami oil and soybean oi) are used. Where necessary, a suitable suspending agent, such as sodium carboxymethylcellulose, nonionic surfactant and solubilizer (e.g., benzyl benzoate, benzyl alcohol and the like) may be used concurrently. Further, when an eye drop or nasal drop is given, an aqueous liquid or aqueous solution is used, particularly, sterile aqueous solution for injection. The liquid for eye drop or nasal drop may contain various additives as appropriate, such as buffer (borate buffer, acetate buffer, carbonate buffer and the like are preferable for reducing irritation), isotonicity agent, solubilizer, preservative, viscous agent, chelating agent, pH adjusting agent (pH is preferably adjusted generally to about 6-8.5) and aromatic.
The amount of the active ingredient in these preparations is 0.1-100 wt %, suitably 1-50 wt %, of the preparation. The dose varies depending on the condition, body weight, age and the like of patients. In the case of oral administration, it is generally about 0.01-50 mg per day for an adult, which is administered once or in several doses.